WHO/PQT: medicines

Guidance Document
01 November 2014

General Notes on Biopharmaceutics Classification System (BCS)-

based Biowaiver Applications

In the WHO Prequalification Team: medicines (PQTm), biowaivers based on the Biopharmaceutics Classification
System (BCS) are intended only to investigate bioequivalence and do not apply to other bioavailability or
pharmacokinetic studies.

1. BACKGROUND
The information presented in this guidance is based on:

a) WHO “Multisource (generic) pharmaceutical products: guidelines on registration requirements to

establish interchangeability. Technical Report Series 937, Annex 7, 2015

b) US FDA "Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for
Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification
System, 2000", available at:
http://www.fda.gov/OHRMS/DOCKETS/98fr/3657gd3.pdf

c) European Medicines Agency (EMA) “Guideline on the Investigation of Bioequivalence”, 2010,

available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC50007
0039.pdf

In principle, highly soluble active pharmaceutical ingredients (APIs) with known human absorption/permeability
characteristics have been identified as eligible for the BCS-based biowaiver approach for establishing the safety
and efficacy of a multisource finished pharmaceutical product (FPP). Therefore, both BCS Class I (high solubility
and high permeability) and Class III (high solubility and low permeability) APIs are considered to be eligible in
cases where sufficient information concerning the API is available to complete an accurate risk-based
assessment for the use of this approach.
In order to maximize opportunities to use BCS-based biowaivers, PQTm has established a two-pronged approach
for biowaiver applications as follows: (1) for products containing APIs for which PQTm has assigned a BCS
classification (see below), a BCS-based biowaiver application can be made without providing data for
classification of the API; and (2) for products containing APIs not included in the table below, a BCS-based
biowaiver application can be submitted if it contains the solubility and absorption/permeability data necessary to
properly classify the API(s) as either BCS Class I or III.

Option 1: Eligible APIs assigned a BCS classification by PQTm

Based on the scientific principles outlined in the guidelines listed above, PQTm has reviewed the available data
related to the solubility, absorption, and dissolution characteristics of the medicinal products invited for PQTm
evaluation, and has identified the following APIs to be eligible for BCS-based biowaiver applications:

General Notes onBiopharmaceutics Classification System (BCS)-

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based Biowaiver Applications

WHO/PQT: medicines
Guidance Document
01 November 2014

Active pharmaceutical
Therapeutic group Highest oral dose [mg] BCS Class
ingredient (API)

Abacavir (as sulfate) Antiretroviral 600 III

Emtricitabine Antiretroviral 200 I

Lamivudine Antiretroviral 300 III

Stavudine Antiretroviral 40 I

Zidovudine Antiretroviral 300 I

Linezolid Antibacterial 600 I

Fluconazole*
Antifungal 800 I
(Polymorphs II & III)

Ethambutol Anti-tuberculosis 400 III

Isoniazid Anti-tuberculosis 300 III

Levofloxacin Anti-tuberculosis 750 I

Moxifloxacin
Anti-tuberculosis 400 I
(as hydrochloride)

Ofloxacin Anti-tuberculosis 400 I

Pyrazinamide Anti-tuberculosis 500 III

Diethylcarbamazine Anti-parasitic 500 III**

* - Fluconazole polymorph I does not fulfill the requirements for BCS high solubility.
** - Insufficient information was available to determine the absorption/permeability classification of diethylcarbamazine (DEC),
therefore DEC has been assigned the provisional classification of Class III. If adequate absorption/permeability data can be
provided in an application, as described below, finalization of the classification as either Class I or III can be undertaken.

Option 2: Full biowaiver application for APIs not assigned to a BCS class by PQTm
PQTm invites interested manufacturers to submit the data necessary to accurately classify an API(s) as a part of
a BCS-based biowaiver application for a FPP containing that API(s). As above, to be eligible for a BCS-based
biowaiver, it must be established that the API is a BCS Class I or III drug substance.
BCS-based biowaiver applications for this option must include complete API solubility and absorption information
consistent with the requirements described in Section III of Annex III of the EMA Guideline on the Investigation of
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Bioequivalence (2010). These data and information should be summarized in the appropriate sections of the
Biowaiver Application Form: Biopharmaceutics Classification System (BCS) with appropriate references to the
detailed data provided in annexes to the application form.

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Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf

General Notes onBiopharmaceutics Classification System (BCS)-

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based Biowaiver Applications

WHO/PQT: medicines
Guidance Document
01 November 2014

2. GENERAL REQUIREMENTS
BCS-based biowaivers are applicable for immediate-release solid oral dosage formulations containing one or
more of the API(s) mentioned above if the required data ensure the similarity of the submitted pharmaceutical
product and the appropriate pharmaceutically equivalent comparator product. Until further notice, in vivo
bioequivalence studies are required for invited monocomponent and fixed-dose combination products containing
other APIs.
Comparator products used in BCS-biowaiver applications should be selected from the current list of PQTm
recommended comparator products, including the appropriate fixed-dose combination product.
Biowaiver-based dossiers should contain relevant information and data as outlined in the following paragraphs:

3. COMPARATOR PRODUCT SUITABILITY

Identification by PQTm of an API to be eligible for a BCS-based biowaiver application is made purely on the
solubility, absorption, safety and related properties of the API (Class I or Class III). It does not imply that the
recommended comparator product(s) will be rapidly dissolving in the case of Class I APIs or very rapidly
dissolving in the case of Class III APIs, which is a requirement for BCS-based biowaiver studies. The applicant
must thus ensure that the recommended comparator(s) listed on the PQTm website is indeed suitable for a BCS
based-biowaiver application before product development.
Note that rapidly dissolving, or very rapidly dissolving, properties of a product are not required for in vivo
bioequivalence studies. Thus, though a listed comparator product may not be suitable for BCS-based biowaiver
purposes, it is still suitable for in vivo bioequivalence studies.

4. FINISHED PHARMACEUTICAL PRODUCT (FPP) CRITERIA

4.1 “Biobatch” selection
As with all FPP applications, the consistency of the manufacturing method and the quality of the test product
must be demonstrated in the relevant sections of the quality part of the dossier.
It is recommended that samples of the test product be taken from batches of industrial scale. However, when
this is not possible, a batch of 1/10 or larger of the expected full production batch, or 100 000 units,
whichever is greater, can also be used as the test product, provided these batches are the same as the
production batches in manufacturing method, quality and composition.
The API content or potency of the comparator product should be close to the label claim, and the difference
in API content or potency between the test and comparator products should be not more than 5%.

4.2 Excipients
BCS Class 1 APIs
In order to minimize the possible impact of excipients on the bioavailability of the API, it is a significant asset
to a biowaiver application if the proposed (test) product contains similar amounts of the same excipients as
the comparator product. Information related to this issue is usually available from public sources of stringent
regulatory authorities (SRAs). At a minimum, well-established excipients in usual amounts should be
employed and possible interactions affecting drug bioavailability and/or solubility characteristics should be
discussed. Excipients that may affect the bioavailability of the API (e.g. mannitol, sorbitol, surfactants) should
be used with care, and if present, should not differ qualitatively and quantitatively between the proposed
product and the comparator product.

General Notes onBiopharmaceutics Classification System (BCS)-

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WHO/PQT: medicines
Guidance Document
01 November 2014

BCS Class 3 APIs

For BCS Class 3 APIs, excipients in the proposed product formulation must be qualitatively the same and
quantitatively very similar to that of the comparator product, except excipients that may affect the
bioavailability of the API (e.g., mannitol, sorbitol, surfactants) which should not differ qualitatively or
quantitatively between the proposed product and the comparator product. The term ‘very similar’ is defined
as per ‘Level 1 Changes’ according to the SUPAC (Scale-Up and Postapproval Changes, US FDA)
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guidance.
In addition, with respect to isoniazid-containing products, lactose and/or other ’reducing sugars’ should not
be included in the formulation of the proposed product unless present in the same amount in the comparator
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product.

5. COMPARATIVE IN-VITRO DISSOLUTION

Dissolution tests should be performed using more than one batch (12 tablets per batch for each study) of the
appropriate comparator product, if possible, using the mean data of these batches for profile comparison. The
“mean data” is the average of the individual batch data of the comparator batches for each pH medium studied
i.e. one set of data and one profile is derived from the multiple batches for each medium and compared against
the test biowaiver batch data and profile. Compilation of ‘historical’ data is not acceptable.
Comparative in vitro dissolution should ensure the similarity of the test and comparator product in three different
pH media considered relevant for absorption in the gastrointestinal tract. Discussion and/or interpretation of
relevant differences between dissolution profiles as to their in vivo relevance is considered inappropriate since, in
the framework of BCS-based biowaivers, respective investigations do not represent any in vitro/in vivo correlation.
Comparative in vitro dissolution should be performed with 12 units of actual batches in 900 ml or less of standard
buffer media at pH 1.2, 4.5 and 6.8, at 37ºC ± 0.5ºC, using the paddle apparatus at 75 rpm or less, or the basket
apparatus at 100 rpm. Surfactants should not be used. Samples should be filtered immediately to prevent
continuation of dissolution. The filters can be in-line or at the end of the sampling probe or both. The sampling
intervals should be short for a scientifically sound comparison of the profiles (e.g. 5, 10, 15, 20, 30 and 45
minutes). Inclusion of the 15-minute time point in the protocol is of strategic importance for profile similarity
determinations.

The following definitions will apply:

• "‘very rapidly” dissolving products: at least 85 % of the labelled amount is released within 15 minutes or
less from the test and the comparator product. In this case profile comparison is not needed.
• “rapidly” dissolving products: at least 85 % of the labelled amount is released within 30 minutes or less
from the test and the comparator product; profile comparisons using e.g. f2 testing, are required.

The experimental setting should be qualified according to current standards, and analytical methods should be
fully validated and comprehensively described. Regarding validation acceptance criteria and method details for
dissolution assays, clear and traceable cross-referencing to the quality part of the dossier is acceptable.

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Guidance for Industry: Immediate Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and
Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation available at:
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070636.pdf
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Becker et al. Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Isoniazid. Journal of Pharmaceutical Science, 96
(2007) 522.

General Notes onBiopharmaceutics Classification System (BCS)-

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WHO/PQT: medicines
Guidance Document
01 November 2014

BCS Class I APIs

For BCS Class I APIs, the test and comparator products must display either very rapid or similarly rapid in vitro
dissolution characteristics under the defined conditions in order to be eligible for a biowaiver.

BCS Class III APIs

For BCS Class III APIs, the test and comparator products must display very rapid in vitro dissolution
characteristics under the defined conditions in order to be eligible for a biowaiver.
For further guidance on biowaiver dissolution conditions and requirements and for determination of similarity of
dissolution profiles, please consult:
WHO “Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish
interchangeability. Technical Report Series 937, Annex 7, 2015

5.1 Format of in vitro dissolution study report

The report on a dissolution study used in the biowaiver application should include a study protocol and at
least the following information:

1. Purpose of study
2. Products / batch information
a. Batch numbers, manufacturing and expiry dates, batch size of the test product, Certificates of Analysis
(CoAs) and packaging of the batches used in the study
b. Batch manufacturing record(s) for the batch of the test product used in the comparative dissolution
study.
3. Full dissolution conditions and method, as well as the number of units (tablets, capsules, etc) per study.
It should be indicated how and when the samples were filtered. Any problems with pH-related stability of
samples should be indicated and discussed in terms of preventive handling measures, analysis and
interpretation of data.
4. Analytical method including validation, or reference to the quality part of the dossier.
5. Results (% API dissolved)
a. Tabulated (individual results, mean and %CV)
b. Graphically
c. Similarity determination / f2 calculation if necessary and applicable
6. Conclusion/recommendation.

6. DOCUMENTATION REQUIRED FOR SUBMISSION

The Biowaiver Application Form: Biopharmaceutics Classification System (BCS) must be completed and
submitted in MS Word format. The instructions for completion of the biowaiver application form are provided at the
top of the form. All supporting documentation including comparator product information, Certificates of Analysis,
and the comparative dissolution study report should be provided as annexes to the application form.

General Notes onBiopharmaceutics Classification System (BCS)-

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based Biowaiver Applications